17 α-(substituted-methyl)-17β-hydroxy/esterified hydroxy steroids and their progestational use

ABSTRACT

Steroids of the formula: ##STR1## which are characterized by a 17α-cyanomethyl, azidomethyl, methoxymethyl, phenylmethyl, or ethynylmethyl substituent and a 17β-hydroxy/esterified hydroxy substitutent. The steroids of this invention have glucocorticoid, anti-glucocorticoid, progrestational, or anti-progestational activity, depending on the particular structure.

This is a continuation, of application Ser. No. 06/908,288, filed Sept.17, 1986; now U.S. Pat. No. 4,774,236.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the field of steroids, and inparticular, to 17α-(substituted-methyl) steroids represented by partialformula (II), wherein Z is selected from residues represented by partialformulas (III) and (IV), which structures possess a variety of valuablebiological properties including glucocorticoid and anti-glucocorticoid,progestational and antiprogestational activities. The invention is alsodirected to pharmaceutical compositions containing the steroidsdisclosed in this invention.

2. Description of the Background Art

M. Hubner, K. Ponsold, M. Oettel and R. Freund, [Arzneim.-Forsch, DrugRes. 30: 401-406 (1980)] described the preparation of17β-hydroxy-17α-(substituted-methyl) derivatives of estra-4,9-dien-3-one(I; R=H, R¹ =Me) and gona-4,9-dien-3-one (I; R=Me, R¹ =Et) in which thesubstituents were:

R¹ =Me; X=N₃, CN, Br, Cl

R¹ =Et; X=N₃.

These structures were characterized as progestational agents. Inparticular, when R=H, R¹ =Me and X=CN, the steroid designated STS 557was obtained which had ten times the oral potency of levonorgestrel as agestagen (M. Hubner and K. Ponsold, Exper. Clin. Endocrinol. 81: 109-114[1983]). Incubation of STS 557 with female rat liver microsomes led toisolation, inter alia, of the metabolite17α-cyanomethyl-11β,17β-dihydroxyestra-4,9-dien-3-one (II; R=H, R¹ =Me,R² =α-H,β-OH, Z=III, R³ =H) but no biological activity was reported forthis product (Exper. Clin. Endocrinol. 81: 168-174 [1983]). This productis excluded from the claims of this invention.

In Eur. Pat. Appln. E.P.129,499 (1984), G. Neef, G. Sauer, R. Wiechert,S. Beie, D. Henderson and R. Rohde describe steroids of type (V) whereinthe substituted-methyl group at C17 is introduced via 17-oxointermediates. The compounds of that invention are characterized by a13α-methyl substituent and thus fall outside the present claims whichrequire a 13β substituent.

In U.S. Pat. No. 4,447,424 to J. G. Teutsch, D. Philibert and R. Deraedtare disclosed steroids of structure (II) wherein the substituents are asfollows:

    ______________________________________                                        R     R.sup.1    R.sup.2 [α-H,β =                                                                 X                                              ______________________________________                                        H     Me         .C.sub.6 H.sub.4 s(CH.sub.2).sub.2 N<                                                       CN                                             H     Me         .C.sub.6 H.sub.4 --N<                                                                       CH.sub.2 C.tbd.CH                              H     Me         .C.sub.6 H.sub.4 C.sub.6 H.sub.4 --N<                                                       CH.sub.2 C.tbd.CH                              H     Me         .C.sub.6 H.sub.4 OCH.sub.2 CH.sub.2 N<                                                      CH.sub.2 C.tbd.CH                              H     Me         .C.sub.6 H.sub.4 SCH.sub.2 CH.sub.2 N<                                                      CH.sub.2 C.tbd.CH                              H     Me         .C.sub.10 H.sub.6 N<                                                                        CH.sub.2 C.tbd.CH                              ______________________________________                                    

and Z=(III); where R³ =H. These structures are claimed to haveanti-glucocorticoid properties. They are excluded from the claims of thepresent invention.

U.S. Pat. No. 3,906,096 to Bucourt et al is directed to steroidalcompounds which have anti-androgenic and anti-estrogenic activities. Thecompounds of Bucourt et al are different from the present compounds inthat the former have an alkoxy group at the 11 position. Further, thecompounds of Bucourt et al do not include the Δ⁴,9 series of compoundsas in this invention, nor does the reference disclose a 17α substituentcontaining a hetero atom.

U.S. Pat. No. 4,540,686 to Philibert et al discloses compounds havinganti-glucocorticoid activity. This reference does not disclose 17αsubstituents containing a hetero atom such as azidomethyl ormethoxymethyl.

U.S. Pat. No. 4,547,493 to Teutsch et al is directed to steroidalcompounds which have anti-glucocorticoid activity. The Δ⁴,9 steroids ofTeutsch et al require a substituent other than hydrogen at the 2position of the steroid ring system, and therefore the compounds of thereference fall outside of the scope of the present claims.

U.S. Pat. No. 4,233,296 to Teutsch et al is directed to11β-substituted-Δ⁴,9 -estradienes having progestomimetic activity. Theonly 17β substituted methyl substituent is a 2-propynyl group.

Although a large group of steroidal compounds with biological activityis known, as evidenced by the above-described disclosures, there remainsa need to discover new and more effective steroidal compounds possessingbiological activity, particularly glucocorticoid/anti-glucocorticoid orprogestational/anti-progestational activity.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide novelsteroidal compounds possessing glucocorticoid activity;

It is another object of the present invention to provide novel steroidalcompounds having anti-glucocorticoid activity;

It is yet another object of the present invention to provide steroidalcompounds having progestational activity;

It is yet another object of the invention to provide novel steroidalcompounds having anti-progestational activity.

These and other objects of the invention as will hereinafter become moreapparent have been accomplished by providing novel 11β-substitutedderivatives of 17α-(substituted-methyl) steroids (II) wherein Z isselected from partial structures (III) and (IV), which compounds possessbinding affinities to glucocorticoid and to progestational receptors. Byvirtue of such binding, these compounds possess biological activities inwarm-blooded animals. The biological activities are glucocorticoid,anti-glucocorticoid, progestational or anti-progestational activities.This surprising range of biological activities of the products of thepresent invention stems from overlap in the structural requirements forbinding to glucocorticoid and progesterone receptors, and represents animportant feature of the present invention.

This invention provides for the first time novel

    ______________________________________                                        17α-Cyanomethyl-                                                                            (II; X = CN),                                             17α-Azidomethyl-                                                                            (II; X = N.sub.3),                                        17α-Thiocyanomethyl                                                                         (II; X = SCN),                                            17α-Methoxymethyl                                                                           (II; X = OMe), and                                        17α-Phenylmethyl (benzyl)                                                                   (II; X = Ph)                                              ______________________________________                                    

derivatives of (II) wherein Z is selected from partial structures (III)and (IV). In addition it provides for the first time novel

17α-Ethynylmethyl (II; X=CH₂ C.tbd.CH) derivatives of (III) providingthe substituent R² does not contain N or S in the molecule. Of these,the 17α-cyanomethyl, 17α-azidomethyl and 17α-methoxymethyl derivativesare preferred. Functional equivalents of these 17α substituents, such asphenyl substituted by C₁ -C₃ alkyl, and substituted methoxy (e.g., CF₃O-) or ethoxy are also within the scope of this invention, provided theyretain the desired activity.

In its broadest embodiment, the present invention covers the abovegeneralized structures, wherein:

R is H, acyl (C₁ -C₁₀), lower alkyl (C₁ -C₃);

R¹ is methyl or ethyl;

R³ is H or methyl; and R² is selected from the group consisting of oxo,11α-hydrogen, 11β-

OH, except when X=CN and R is H

lower alkyl (C₁ -C₁₀);

lower alkenyl (C₁ -C₁₀), with the understanding that when C=1, thealkenyl group is methylene and is attached directly to position C₁₁ ;

lower alkynyl (C₁ -C₁₀);

C₆ H₅ and --C₆ H₄.R⁴ ;

(CH₂)n·R⁵ wherein n is 1 to 4;

pyridyl;

thiazolyl;

piperidinyl;

wherein R⁴ is selected from the group consisting of

H, ##STR2## --NMe₂,

OCH₂ CH₂ NMe₂ (Et₂);

lower alkyl (C₁ -C₃);

O-lower alkyl (C₁ -C₃);

halogen;

CF₃ ;

C₆ H₅ ;

S-lower alkyl or -phenyl;

and R⁵ is selected from the group consisting of ##STR3##

The receptor-binding affinities and biological properties of theforegoing class of steroids fall generally into 4 main groups:

Group I

Compounds in this group have binding affinity for the glucocorticoidreceptor and generally possess glucocorticoid, and in particular,topical glucocorticoid activity. These structures (II) wherein Z isselected from partial structures (III) or (IV) are characterized bysubstituents selected from the following:

R is H or lower acyl and in particular acetyl, propionyl, and butyryl;

R¹ is methyl;

R² is α-H, β-OH (except where X=CN) or =O; and

R³ is H.

Group II

Compounds in this group have binding affinity for the glucocorticoidreceptor and generally possess antiglucocorticoid activity. Thesecompounds [(II; wherein Z has partial structure (III)] are characterizedby the following substituents:

R is H or lower acyl and in particular acetyl, propionyl, and butyryl;

R¹ is methyl or ethyl; and

R² is α-H and an 11β-substituent as hereinabove defined containing N orS in the molecule except when X=--C.tbd.CH. Preferred substituents areselected from the group consisting of: ##STR4##

Of the 17α-methyl substituents in Group II --OCH₃ and N₃ are preferred,and N₃ is most preferred.

Group III

Compounds of this group have binding affinity for the progesteronereceptor and generally possess progestational activity. These compounds[II; wherein Z has partial structure (III)] are characterized bysubstituents selected from the following:

R is H or lower acyl and in particular acetyl, propionyl, and butyryl;

R¹ is methyl or ethyl;

R² is α-H and β is lower alkyl such as, for example, methyl, ethyl, andn-propyl;

R² is α-H and β is lower alkenyl such as, for example, methylene, vinyl,propenyl, allyl, and isopropenyl;

R² is α-H and β is aryl such as, for example, phenyl, p-methoxyphenyl,p-fluorophenyl, and trifluoromethylphenyl;

R² is α-H, β-thienyl;

R² is α-H, β-trifluoromethyl; and

R³ is H or methyl.

Of the 17α-methyl substituents in Group III, --CN, --OCH₃ and --N₃ arepreferred. Of these, --OCH₃ and --N₃ are more preferred.

Group IV

Compounds of this group have binding affinity for the progesteronereceptor and generally posess antiprogestational activity. Thesecompounds [II; wherein Z has partial structure (III)], are characterizedby the following substituents:

R is H or lower acyl and in particular acetyl, propionyl and butyryl;

R¹ is methyl or ethyl;

R² is α-H and an 11β substituent as hereinabove defined containing N orS in the molecule except when X=--C.tbd.CH. Preferred substituents areselected from the group consisting of: ##STR5##

Of the 17α methyl substituents, CN is preferred.

Compounds in Groups II and IV which contain a basic center may beconverted into their non-toxic, pharmacetuically acceptable acidaddition salts, which are regarded as falling within the scope of thepresent invention. Examples of suitable acids include hydrochloric acid,sulfuric acid, phosphoric acid and organic acids such as acetic,propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, lactic,toluenesulfonic, adipic, aspartic, and isethionic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows steroid structures and partial structures I-VII which aredescribed in greater detail herein.

FIG. 2 shows the structures of compounds VIII-XIV which are described ingreater detail herein.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Generally, of the 17α methyl substituents, those containing a heteroatom are preferred. For example, CN, N₃, SCN, OMe are the methylsubstituents at the 17α position which are preferred.

Specific, preferred compounds of this invention are as follows:

    ______________________________________                                                                                  Oth-                                Compound                                                                              W       X         Y         Z     er                                  ______________________________________                                         ##STR6##                                                                     ______________________________________                                        XVI     OH      N.sub.3   α-H,β-OH                                 XVII    OH      OCH.sub.3 α-H,β-OH                                 XVIII   OH      N.sub.3   O                                                   XIX     OH      OCH.sub.3 O                                                   ______________________________________                                         ##STR7##                                                                     ______________________________________                                        XX      OH      N.sub.3   α-H,β-OH                                                                           Δ.sup.1                       XXI     OH      OCH.sub.3 α-H,β-OH                                                                           Δ.sup.1                       XXII    OH      N.sub.3   α-H,β-OH                                                                           --                                  XXIII   OH      OCH.sub.3 α-H,β-OH                                                                           --                                  XXIV    OH      N.sub.3    O              Δ.sup.1                       XXV     OH      OCH.sub.3 O               Δ.sup.1                       XXVI    OH      N.sub.3   O               --                                  XXVII   OH      OCH.sub.3 O               --                                  ______________________________________                                         ##STR8##                                                                     ______________________________________                                        XVIII   OH      CN                                                                                       ##STR9## H                                         XXIX    OH      N.sub.3                                                                                  ##STR10##                                                                              H                                         XXX     OH      OCH.sub.3                                                                                ##STR11##                                                                              H                                         XXXI    OH      CN                                                                                       ##STR12##                                                                              H                                         XXXII   OH      N.sub.3                                                                                  ##STR13##                                                                              H                                         XXXIII  OH      OCH.sub.3                                                                                ##STR14##                                                                              H                                         XXXIV   OH      CN                                                                                       ##STR15##                                                                              CH.sub.3                                  XXXV    OH      N.sub.3                                                                                  ##STR16##                                                                              CH.sub.3                                  XXXVI   OH      OCH.sub.3                                                                                ##STR17##                                                                              CH.sub.3                                  XXXVII  OH      CN                                                                                       ##STR18##                                                                              CH.sub.3                                  XXXVIII OH      N.sub.3                                                                                  ##STR19##                                                                              CH.sub.3                                  XXXIX   OH      OCH.sub.3                                                                                ##STR20##                                                                              CH.sub.3                                  ______________________________________                                         ##STR21##                                                                    ______________________________________                                        XL      OH      CN        α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLI     OH      N.sub.3   α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLII    OH      OCH.sub.3 α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLIII   OH      CCH       α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLIV    OH      N.sub.3   α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLV     OH      OCH.sub.3 α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLVI    OH      CCH       α-H,                                                                              H                                                                   β-CHCH.sub.2                                   XLVII   OH      N.sub.3   α-H,                                                                              α-CH.sub.3                                                    β-CHCH.sub.2                                   ______________________________________                                    

Preparation of Compounds of the Present Invention

The compounds of the present invention are readily prepared fromappropriate 17-oxo precursors of partial structure (VI) by reaction withmethylide reagents such as, for example, trimethyl sulfonium iodide andsodium hydride in a solvent such as dimethylsulfoxide, to yield theoxiranes (VII) (C. E. Cook, R. C. Corley, M. E. Wall, J. Org. Chem. 33:2789 [1968]). The latter are then converted into the substituted methylderivatives (II) by the method of K. Ponsold, M. Hubner, W. Schade, M.Oettel and R. Freund [Pharmazie 33:792 (1965)].

In preparing compounds of type (II) wherein Z=IV), enol ethers such as(VIII) may be conveniently employed as starting materials. Thesecompounds react readily with methylide reagents to give the oxiranes(IX) which may be converted into substituted methyl derivatives (X) byconventional methods. Dilute acid hydrolysis of (X) yields the 3-oxo-Δ⁴-ketones of partial structure (IV), which may be converted into Δ¹-derivatives by standard procedures if so desired.

Compounds of type (II), wherein R=H, R¹ =Me, R² =α-H,β-OH and Z isrepresented by partial formula (IV) with a Δ¹ -unsaturated linkage arereadily prepared from steroid (XI) which is well known in the art [G.Teutsch, G. Costerousse, R. Deraedt. J. Benzoni, M. Fortin and D.Philibert, Steroids 38: 651-665, (1981)]. This intermediate reacts withmethylide reagents to give the oxirane of partial structure (VII; R¹=Me). The latter can then be converted into structures [II; X is ashereinabove defined, R=H, R¹ =Me, R² =α-H,β-OH, Z is IV; Δ¹)] byconventional methods as herein above defined.

In preparing compounds of type (II) wherein Z=(III), it is preferred touse the 5α-hydroxy intermediate (XII) as starting material. Compound(XII) reacts readily with methylide reagents to give the oxiranes (XIII)which may be converted into 17α-(substituted-methyl) steroids (XIV) byknown methods. Mild acid hydrolysis of intermediate (XIV) results inloss of the ketal protecting group with concomitant dehydration to givestructures (II) wherein Z=(III).

EXAMPLE 117α-Cyanomethyl-11β-(4-dimethylaminophenyl)-17β-hydroxy-4,9-estradien-3-oneStep A:3,3-Ethylenedioxy-ε-trimethylsilyloxy-17ε-cyano-11β-(4-dimethylaminophenyl)-9-estren-5α-ol

To a stirred solution of magnesium (13.124 gm, 0.54 g atom) in drytetrahydrofuran (179 ml) was added a small crystal of iodine. A solutionof 4-bromo-N,N-dimethylaniline (44.72 g, 0.22 mol) and 1,2-dibromoethane(18.75 ml, 0.12 mol) in dry tetrahydrofuran (179 ml) was added at a rateto maintain reflux. Upon completion of the addition, the reactionmixture was heated at 50°-55° C. for 2.5 h, cooled to room temperatureand cuprous bromide-dimethyl sulfide complex (11.54 g, 0.056 mol) wasadded. After the reaction mixture was stirred for an additional 30 min.,more tetrahydrofuran (179 ml) was added. This was followed by additionof3,3-ethylenedioxy-17ε-trimethylsilyloxy-17ε-cyano-9,11-estrene-5ε,10ε-epoxide(18.98 g) ]J. C. Gasc and l. Nedelec, Tetrahedron Lett., 2005 (1971)] indry tetrahydrofuran (179 ml). After 2 h, the reaction mixture was pouredinto a vigorously stirred solution of saturated ammonium chloride (1.8L). The phases were separated and the aqueous phase was re-extractedwith ether. The crude residue (22.17 g) from the dry ether layer waspartially purified by elution from silica gel 60 (200-430 mesh) using agradient of methylene chloride/triethylamine (99.9:0.1) and methylenechloride/acetone/triethylamine (97.4:2.5:-0.1). Rechromatography usingthe same system gave 3.7 g of the 17β-cyano isomer and 1.78 g of the17α-cyano isomer. β-cyano isomer: ¹ HNMR (CDCl₃, 60 MHz) δ 0.25 [s,Si(CH₃)₃ ], 0.55 (s, 18-CH₃), 2.88 [s, N(CH₃)₂ ], 3.93 [2, --O--(CH₂)₂--O--], 4.23 (m, 11-H), 4.33 (s, 5-OH), 6.51 (d, J=9 Hz, Ar-H ortho todimethylamino), 6.94 (d, J=9 Hz, Ar-H meta to dimethylamino); IR (CH₂Cl₂) 1615 (C═C), 2947 (saturated hydrocarbon), 3505 cm⁻¹ (5-OH); massspectrum (70 eV) m/z (rel intensity) 550.3225 (12), 532 (100), C₃₂ H₄₆O₄ N₂ Si requires an M⁺ at m/z 550.3226. α-cyano isomer: ¹ H NMR (CDCl₃,60 MHz) δ 0.23 [s, si(CH₃)₃ ], 0.47 (s, 18-CH₃), 2.85 [s, N(CH₃)₂ ],3.90 ]s, --O--(CH₂)₂ --O--], 4.15 (s, 5-OH), 4.22 (m, 11-H), 6.52 (d,J=9 Hz, Ar-H ortho to dimethylamino), 6.93 (d, J=9 Hz, Ar-H meta todimethylamino). IR (CH₂ Cl₂) 1612 (C═C), 2950 (saturated hydrocarbon),3510 cm⁻¹ (5-OH); mass spectrum (70 eV) m/z (rel intensity) 550.3225(8.0), 532 (100.0).

Step B:3,3-Ethylenedioxy-11β-(4-dimethylaminophenyl)-5α-hydroxy-9-estren-17-one

The mixture of isomers at C-17 obtained in Step A (12.4 g, 22.55 mmol)was dissolved as completely as possible in methanol (900 ml). Sodiumhydroxide (10N, 100 ml) was added and the reaction mixture was stirredfor 1 h at room temperature. It was then poured into distilled water(2.5 L) and the resulting precipitate extracted with methylene chloride.The methylene chloride extract was washed twice with distilled water andsaturated sodium chloride and dried (Na₂ SO₄). Solvents were flashevaporated, and the residue was dried in vacuo to afford the titleketone (7.66 g, 75.3%). ¹ H NMR (CDCl₃, 60 MHz) δ 0.50 (s, 18-CH₃), 2.87[s, N(CH₃)₂ ], 3.92 ]s, --O--(CH₂)₂ --O--], 4.17 (m, 11-H), 4.25 (s,5-OH), 6.50 (d, J=9 Hz, Ar-H ortho to dimthylamino), 6.93 (d, J= 9 Hz,Ar-H meta to dimethylamino); IR (CH₂ Cl₂) 1735 (17-carbonyl), 2940(saturated hydrocarbon) and 3520 cm⁻¹ (5-OH); mass spectrum (70 eV) m/z(rel intensity) 451.2720 (13), 433 (100), C₂₈ H₃₇ O₄ N requires an M⁺ atm/e 451.2722.

Step C:3,3-Ethylenedioxy-11β-(4-dimethylaminophenyl)spiro-17β-oxiranyl-9-estren-5α-ol

The title compound was obtained in 86% from the ketone of Step Bfollowing an analogous procedure of Cook et al. [J. Org. Chem. 33, 2789(1968)]. ¹ H NMR (CDC]₃, 60 mHz) δ0.50 (s, 18-CH₃), 2.85 [s, N(CH₃)₂ ],3.92 [2, --O--(CH₂)₂ --O--], 4.12 (m, 11-H), 4.23 (s, 5-OH), 6.48 (d,J=9 Hz, Ar-H ortho to dimethylamino), 6.87 (d, J=9 Hz, Ar-H meta todimethylamino); IR (CH₂ Cl₂) 1612 (C═C), 2940 (saturated hydrocarbon),3510 cm⁻¹ (5-OH); mass spectrum (70 eV) m/z (rel intensity) 465.2878(4), 447 (36), 191 (100), C₂₉ H₃₉ O₄ N requires an M⁺ at m/z 465.2879.

Step D:3,3-Ethylenedioxy-11β-(4-dimethylaminophenyl)-17β-hydroxy-17.alpha.-cyanomethyl-9-estren-5α-ol

The title compound was obtained in 47% yield from the oxirane of Step Cfollowing an analogous procedure to that of Wagner et al. [J. LabelledCompd. Radiopharm., 17, 317 (1980)] ¹ H NMR (CDCl₃, 60 MHz) δ 0.52 (s,18-CH₃), 2.85 [s, N(CH₃)₂ ], 3.92 [s, --O--(CH₂)₂ --O--], 4.18 (m,11-H), 4.28 (s, 5-OH), 6.50 (d, J=9 Hz, Ar-H ortho to dimethylamino),6.92 (d, J=9 Hz, Ar-H meta to dimethylamino); mass spectrum (70 eV) m/z(rel intensity) 492.2985 (6), 474 (100), C₃₀ H₄₀ O₄ N₂ requires an M⁺ atm/z 492.2988.

Step E:17α-Cyanomethyl-11β-(4-dimethylaminophenyl)-17β-hydroxy-4,9-estradien-3-one

The cyanomethyl derivative obtained in Step D (3.15 g, 6.4 mmol) wasdissolved in N HCl in ethanol (75 ml) and stirred at room temperaturefor 2.5 h. Then the reaction mixture was poured into 500 ml of cold 5%sodium bicarbonate, and the resulting precipitate was extracted withmethylene chloride. The extract was washed with distilled water andsaturated sodium chloride and dried (Na₂ SO₄). Solvents were flashevaporated, and the residue was dried in vacuo to yield 2.63 g of a paleyellow foam. The crude product was crystallized from hot methanol/ethylacetate to yield the title compound as pale yellow crystals in 58%yield. MP (Koefler Hot Stage) around 263°-278° C. (decomposition withgas evolution and previous sweating at 235° C. and formation of moistureat 250° C.); ¹ H NMR (CDCl₃, 60 Hz) δ 0.58 (s, 18-CH₃), 2.85 [s, N(CH₃)₂], 4.30 (m, 11α-H), 5.67 (s, 4-H), 6.50 (d, J=9 Hz, Ar-H ortho todimethylamino), 6.88 (d, J= 9 Hz, Ar-H meta to dimethylamino); IR (CH₂Cl₂) 3610 (hydroxyl), 2950 (saturated hydrocarbon), 2260 (C═N), 1660cm⁻¹ (unsaturated carbonyl); mass spectrum (70 eV) m/z 430.2620 (7), 389(60), 121 (100), C₂₈ H₃₄ O₂ N₂ requires an M⁺ at m/z 430.26260.

Anal. Calcd for C₂₈ H₃₀ O₂ N₂ : C, 78.10; H, 7.96; N, 6.51. Found: C,78.03; H, 8.00; n, 6.48.

EXAMPLE 211β-(4-Dimethylaminophenyl)-17β-hydroxy-17α-azidomethyl-4,9-estradien-3-one

A solution of the oxirane obtained in Step C, Example 1, (150 mg, 0.32mmol) and sodium azide (300 mg, 4.62 mmol) in methanol (3 ml) wasrefluxed for 6 h. The reaction mixture was then cooled to roomtemperature and treated with 4 ml of 1N HCl in ethanol. After 45 min,the reaction mixture was added to 5% sodium bicarbonate and extractedwith methylene chloride. After the extract was washed with water andsaturated sodium chloride solution, it was dried (Na₂ SO₄) and thesolvent evaporated. The resulting residue was purified by preparativethin layer chromatography on silica gel 60 F-254 developed with ethylacetate/triethylamine (99.5:0.5) to yield 31.8 mg (22.1%) of the titlecompound: ¹ H NMR (250 MHz, CDCl₃), δ0.60 (s, 3, 18-CH₃), 2.92 (d, 6,J=0.89 Hz, CH₃ -N-CH₃), 3.27 (d, 1, J= 12.1 Hz, CH-N₃), 3.58 (d, 1,J=12.1 Hz, CH-N₃),4.34 [m (appears as d separated by 6.5 Hz), 1, 11-H],5.76 (s, 1,4-H), 6.66 (d, 2, J=8.5 Hz, Ar-H ortho to CH₃ -N-CH₃, 7.01(d, 2, J=8.5 Hz, Ar-H); mass spectrum (70 eV), m/z (rel intensity)446.2681 (33.0), 418 (24.0), 389 (19.1), 121 (100.0), C₂₇ H₃₄ N₄ O₂requires an M⁺ at m/z 446.2681.

EXAMPLE 311β-(4-Dimethylaminophenyl)-17β-hydroxy-17α-methoxymethyl-4,9-estradien-3-one

A solution of the oxirane of Step C, Example 1, (25 mg, 0.054 mmol) andsodium hydroxide (25 mg) in methanol (1 ml) was stirred at 50°-55° C.for 24 h. An additinal 50 mg of sodium hydroxide was then added andheating was continued for a total of 48 h. The reaction mixture wasdiluted with distilled water, and the resulting precipitate wasextracted with methylene chloride. After the extract was washed withwater (3X) and saturated sodium chloride solution, it was dried (Na₂SO₄) and the solvent was evaporated. The resulting residue was stirredwith N HCl in ethanol (1 ml) for 45 min at room temperature, neutralizedwith aqueous sodium bicarbonate and extracted with methylene chloride.The residue from the dry methylene chloride layer was purified byreverse phase chromatography using a Lobar® RP-8 column equilibratedwith 20% water in methanol to give the title compound: ¹ H NMR (250 MHz,CDCl₃), δ0.58 (s, 3, 18-CH₃), 2.91 (s, 6, CH₃ -N-CH₃), 3.21 (d, 1, J=9.1Hz, CH-OCH₃), 3.41 (s, 3, OCH₃), 3.55 (d, 1, J=9.1 Hz, CH-OCH₃), 4.31(m, (appears as d separated by 6.6 Hz), 1, 11-H], 5.75 (s, 1, 4-H), 6.65(d, 2, J=8.7 Hz, Ar-H ortho to CH₃ -N-CH₃), 7.02 (d, 2, J=8.7 Hz, Ar-H);mass spectrum (70 eV) m/z (rel intensity), 435.2774 (72.4),280 (11.7),134 (24.1), 121 (100.0), C₂₈ H₃₇ N₁ O₃ requires M⁺ at m/z 435.2773.

EXAMPLE 411β-(4-Dimethylaminophenyl)-17β-hydroxy-17α-benzyl-4,9-estradien-3-one

Boron trifluoride etherate (0.75 ml) was added in a dry atmosphere to asolution of phenyl lithium (3.0 ml of a 1.7M solution in ethylether/cyclohexane 7:3) in tetrahydrofuran (10 ml) at -78° C. After thereaction mixture was stirred for 10 min, the oxirane of Step C, Example1, (125 mg) in tetrahydrofuran (5 ml) was added dropwise over 2 min.After 1 h, more boron trifluoride etherate (0.75 ml) was added. Twohours later the reaction mixture was poured cautiously into coldsaturated ammonium chloride. The resulting solution was stirredvigorously for 30 min at room temperature and then was extracted withmethylene chloride. After the extract was washed with water andsaturated sodium chloride solution, it was dried (Na₂ SO₄) and solventswere evaporated. The resulting residue was chromatographed on a size B(E. Merck) Lobar® RP-8 column (10% H₂ O in methanol) to afford 68 mg(52.7%) of the title compound. .sup. 1 H NMR (CDCl₃, 250 MHz) δ 0.65 (s,3, 18-CH₃), δ 2.37 (m, H--C--Φ), 2.62 (m, H--C--Φ), 2.92 (s, 6, CH₃--N--CH₃), 4.41 (apparent d, 1, 11-H), 5.78 (s, 1, 4-H9, 6.67 (d, 2,J=8.7, Ar-H ortho to CH₃ --N--CH₃), 7.06 (d, 2, J=8.7, Ar-H meta to CH₃--N--CH₃), 7.25-7.35 (m, 4, remaining aromatic protons).

EXAMPLE 511β-(4-Dimethylaminophenyl)-17β-hydroxy-17α-prop-2-yn-1-yl-4,9-estradien-3-one

Under anhydrous reaction conditions in a nitrogen atmosphere, pureacetylene was bubbled for 20 min at -78° C. into tetrahydrofuran (2 ml)containing 0.65 ml of 1.5M n-butyllithium in hexane. Boron trifluorideetherate (0.15 ml) was added and the reaction mixture was stirred for 10min at -78° C. Then oxirane of Step C, Example 1, (25 mg. 0.054 mmol),dissolved in tetrahydrofuran (2 ml) was added under stirring [cf. M.Yamaguchi and I. Hirao, Tetrahedron Lett., 24, 391 (1983)]. After 1 h,more boron trifluoride etherate (0.15 ml) was added. Two hours later thereaction mixture was poured cautiously into cold saturated ammoniumchloride. The resulting solution was stirred vigorously for 15 min atroom temperature and then was extracted with ether. The aqueous phasewas basified to pH 9-10 and was extracted with ether. This extract waswashed with distilled water until the wash was neutral and then oncewith saturated sodium chloride solution and dried (Na₂ SO₄). Solventswere removed by flash evaporation. The resulting residue was purified bypreparative thin layer chromatography on a silica gel plate (20×20×0.25cm, E. Merck) developed with acetone/methylene chloride (2:8) containinga few drops of triethylamine (5 mg, 21.7%). Mass spectrum (70 eV) m/z(rel intensitly) 429.2669 (16.0), 293 (10.7), 149 (100.0), C₂₉ H₃₅ NO₂requires an M⁺ at m/z 429.2668; ¹ H NMR (CDCl₃, 250 MHz), δ 0.62 (s, 3,18-CH₃), 2.37 (s, possibly C.tbd.CH), 2.92 (2, 6, CH₃ --N--CH₃), 4.35 [m(appears as d separated by 6.8 Hz), 1, 11-H], 5.76 (s, 1, 4-H), 6.66 (d,2, J=8.8, Ar-H ortho to CH₃ --N--CH₃), 7.01 (d, 2, J=8.8. Ar-H).

EXAMPLE 6

The compounds corresponding to the products of Examples 1(E), 2, 3, 4and 5 in which the 11β-substitutent is methyl instead of4-N,N-dimethylaminophenyl- are synthesized from the known3,3-ethylenedioxy-17ε-trimethylsilyloxy-17ε-cyano-11β-methyl-9-estren-5α-ol[G. Teutsch, Tetrahedron Lett., 23, 4697 (1982)] using the proceduresdescribed in Examples 1B-E, 2, 3, 4 and 5.

EXAMPLE 717α-Azidomethyl-11β-(4-dimethylaminophenyl)-11β,17β-dihydroxyandrost-1,4-dien-3-one

The title compound is synthesized from 11β-androsta-1,4-diene-3,17-dioneby successive application of the methods of Example 1, Step C andExample 2.

Activity EXAMPLE 8

The in vitro activity of the subject compounds was determined bymeasuring the binding affinities (RBA) of these compounds relative toprogesterone for the progesterone receptor in the cytosol obtained fromestrogen-primed immature rabbit uterus, by measuring the RBA relative todexamethasone for the glucocorticoid receptor from thymus ofadrenalectomized rats and by measuring the RBA relative to estradiol forthe estrogen receptor from immature rat uterus. These assays werecarried out by the procedures of J. R. Reel et al., Fertility andSterility, 31, 552 (1979) (progesterone), G. P. Chrousos et al.,Endocrinology, 107, 472 (1980) (glucocorticoid), and S. G. Korenman etal, J. Clin. Endocrinol., 28, 127 (1968) (estrogen). The results arepresented in Table 1. RBA values greater than 100 indicate a higheraffinity for the receptor than the steroid used as standard. Thus,compounds XVa-XVe have affinity for the progestin receptor with RBA'sabout half that of the natural hormone progesterone. In some cases,especially XVc and XVd, this is accompanied by very strong binding tothe glucocorticoid receptor (ca. 3 times the RBA of the potentcorticosteroid dexamethasone). The compounds do not bind to the estrogenreceptor and thus appear devoid of inherent estrogenic activity.

The strong binding to the glucocorticoid receptor is in surprisingcontrast to the findings of H. Hoffmann et al. [Exper. Clin. Endocrinol.81, 146 (1983)] that the simpler compound Id did not show anyglucocorticoid or antiexudative properties and thus illustrates thesurprising range of biological activities encompassed by the presentseries of compounds compared to the prior art.

EXAMPLE 9 In vivo Antiprogestational Activity

The antiprogestational activity of compound XVa was studied after bothintrauterine and oral administration. In each case the compound wastested for its ability to inhibit the endometrial response due tosubcutaneous administration of progesterone to estrogen-primed immaturefemale rabbits. The methodology used for the intrauterine test has beendescribed by D. A. McGinty et al [Endocrinology, 24, 829 (1939)]. Fororal administration of test compounds the method used was analogous tothat of Clauberg [Clauberg, Zentr. Gynakol, 54, 2757 (1930)] as modifiedby McPhail [J. Physiol. (London) 83, 145 (1935)].

The results of these tests are given in Table 2. They show a clear,dose-related antiprogestational effect. This is again in contrast to theresults found by S. Stolzner et al. [Exper. Clin. Endocrinol., 81, 115(1983)] on the simpler analog I (STS 557) which had strongprogestational activity. It shows the striking influence of the11-substituent on biological activity of the subject compounds.

                  TABLE 1                                                         ______________________________________                                        BINDING AFFINITIES OF COMPOUNDS XVa-XVe FOR                                   PROGESTERONE, GLUCOCORTICOID, AND ESTROGEN                                    RECEPTORS.sup.a                                                                         RBA.sup.b for Receptors                                             Compound    Progestin Glucocorticoid                                                                             Estrogen                                   ______________________________________                                        Progesterone                                                                              100       24           0                                          Dexamethasone                                                                             0.1       100          0                                          Estradiol   --        --           100                                        XVa         33        74           0                                          XVb         71        143          0                                          XVc         54        413          0                                          XVd         64        274          0                                          XVe         23        100          0                                          ______________________________________                                         .sup.a The test procedure involved incubation of test compound (varied        concentrations) with cytosol containing the receptor and a tritiumlabeled     ligand (progesterone, dexamethasone or estradiol). The concentration          required to displace 50% of bound radioligand is determined graphically       and compared with that of an unlabeled standard (progesterone,                dexamethasone or estradiol).                                                  .sup.b These results are the average of 1-3 assays.                           ##STR22##                                                                     -                                                                        

                  TABLE 2                                                         ______________________________________                                        ANTIPROGESTATIONAL ACTIVITY OF XVa.sup.a                                                         Total Dose                                                                              % Inhibition of                                  Compound                                                                              Route      per Rabbit                                                                              Progestational Response                          ______________________________________                                        XVa     Intrauterine                                                                             0         0                                                        Intrauterine                                                                             1.0 μg 7.3 ± 4.5                                             Intrauterine                                                                             5.0 μg 26.7 ± 4.5                                            Intrauterine                                                                             10.0 μg                                                                              80.5 ± 9.8                                            Intrauterine                                                                             40.0 μg                                                                              96.3 ± 3.7                                    XVa     Oral       0         0                                                        Oral       5 mg      7.8 ± 6.0                                             Oral       10 mg     56.2 ± 7.1                                            Oral       20 mg     79.1 ± 7.4                                    ______________________________________                                         .sup.a Immature female rabbits are primed with estrogen and dosed with        progesterone (subcutaneous, 0.8 mg total dose). Uterine tissue is fixed,      stained and scored for endometrial proliferation according to McPhail.   

The compounds of the present invention may be administered by a varietyof methods. Thus, those products of the invention that are active by theoral route may be administered in solutions, suspensions, emulsions,tablets, including sublingual and intrabuccal tablets, soft gelatincapsules, including solutions used in soft gelatin capsules, aqueous oroil suspensions, emulsions, pills, lozenges, troches, tablets, syrups orelixirs and the like. Products of the invention active on parenteraladministration may be administered by depot injection, implantsincluding silastic and biodegradable implants, intramuscular andintravenous injections.

Compositions may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents. Tablets containing the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, such as maize starch, or alginic acid; bindingagents, such as starch, gelatin or acacia; and lubricating agents, suchas magnesium stearate, stearic acid or talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration and adsorptionin the gastrointestinal tract and thereby provide a sustained actionover a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate along or with a wax may beemployed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oil suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredients in admixture with a dispersing or wetting agent,a suspending agent, and one or more preservatives. Suitable dispersingor wetting agents and suspending agents are exemplified by thosedisclosed above. Additional excipients, for example sweetening,flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,such as solution in 1,3-butanediol. Among the acceptable vehicles andsolvents that may be employed are water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile oils may conventionallybe employed as a solvent or suspending medium. For this purpose anybland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may likewisebe used in the preparation of injectables.

The compounds of this invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

They may also be administered by intranasal, intraocular, intravaginal,and intrarectal routes including suppositories, insufflation, powdersand aerosol formulations.

Products of the invention which are preferably administered by thetopical route, and in particular those of Group I, may be administeredas applicator sticks, solutions, suspensions, emulsions, gels, creams,ointments, pastes, jellies, paints, powders, and aerosols.

Products falling within Group I are of particular utility as topicalglucocorticoids of value in the treatment of inflammatory, allergic andother skin conditions, both alone and in combination with an antibioticsuch as neomycin. Products falling within Group II are of particularvalue in pathological conditions characterized by excess endogenousglucocorticoids such as Cushing's syndrome, hirsutism and in particularwhen associated with the adrenogenital syndrome, ocular conditionsassociated with glucocorticoid excess such as glaucoma, stress symptomsassociated with excess glucocorticoid secretion and the like.

Products falling within Group III are of particular value asprogestational agents, ovulation inhibitors, menses regulators,contraceptive agents, agents for synchronizaion of fertile periods incattle, endometriosis, and the like. When used for contraceptivepurposes, they may conveniently be admixed with estrogenic agents, suchas for example as ethynylestradiol or estradiol esters.

Products falling within Group IV are characterized by antagonizing theeffects of progesterone. As such, they are of particular value incontrol of hormonal irregularities in the menstrual cycle and forsynchronization of fertile periods in cattle. They may also beadministered in conjunction with prostaglandins, oxytocics, zoapatanoland the like.

The compounds of the invention may be used for control of fertilityduring the whole of the reproductive cycle. They are of particular valueas postcoital contraceptives, for rendering the uterus inimical toimplantation, and as "once a month" contraceptive agents. They may alsobe used in conjunction with prostaglandins, oxytocics and the like.

A further important utility for the products of the invention lies intheir ability to slow down growth of hormone-dependent cancers. Suchcancers include kidney, breast, endometrial, ovarian cancers, andprostate cancer which are characterized by possessing progesteronereceptors and may be expected to respond to progestational and/oranti-progestational agents. Other utilities of anti-progestationalagents include treatment of fibrocystic disease of the breast. Certaincancers and in particular melanomas may respond favorably tocorticoid/anticorticoid therapy.

The compounds according to the present invention may be administered toany warm-blooded mammal such as humans, domestic pets, and farm animals.Domestic pets include dogs, cats, etc. Farm animals include cows,horses, pigs, sheep, goats, etc.

The amount of active ingredient that may be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aunit dose of the steroid may preferably contain betweeen 0.0001 gramsand 1 gram of the active ingredient. A more preferred unit dose isbetwen 0.001 and 0.1 grams. It will be understood, however, that thespecific dose level for any particular patient will depend on a varietyof factors including the activity of the specific compound employed; theage, body weight, general health, sex and diet of the individual beingtreated; the time and route of administration; the rate of excretion;other drugs which have previously been administered; and the severity ofthe particular disease undergoing therapy, as is well understood bythose of skill in the art.

The invention now being fully described, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit and scope of theinvention as set forth herein.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:
 1. A steroid having binding affinity for theprogesterone receptor and possessing progestational activity,represented by partial formula II, wherein Z has partial structure III,##STR23## wherein: X is selected from the group consisting of, CN, N₃,SCN, OMe, and Ph which is unsubstituted or substituted by C₁₋₃ alkyl;Ris H or C₁ -C₅ acyl; R¹ is methyl or ethyl; R² is α-H and β C₁ -C₃alkyl; or R² is α-H and β C₂ -C₄ alkenyl; or R² is methylene; or R² isα-H and β p-fluorophenyl or trifluoromethylphenyl; or R² is α-H,β-thienyl; and R³ is H or methyl.
 2. A steroid according to claim 1,wherein R is acetyl, propionyl or butyryl.
 3. A steroid according toclaim 1, wherein R² is α-H and β is methyl, ethyl, or n-propyl.
 4. Asteroid according to claim 1, wherein R² is methylene or R² is α-H and βis vinyl, propenyl, allyl, or isopropenyl.
 5. A method of inducing aprogestational hormonal response, which comprises administering aneffective amount of a steroid of claim 1 to a warm-blooded mammal inneed thereof.